Process for preparing ocular lens with urethane compound and process for preparing urethane compound for medical instruments

ABSTRACT

A process for preparing an ocular lens with a urethane compound comprising the steps of  
     a) preparing a urethane compound by reacting at least one hydroxyl compound and at least one isocyanate compound in the presence of an organic iron compound,  
     b) removing the organic iron compound from the urethane compound obtained in the step a)  
     c) mixing the urethane compound obtained in the step b) with at least one compound selected from the group consisting of another copolymerizable compound, a crosslinking agent, a UV absorbent, a dye, a polymerization initiator, a photosensitizer, and an organic solvent to obtain a mixture, and  
     d) curing the mixture obtained in the step c) to prepare a lens.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This is a continuation-in-part of application Ser. No. 09/608,004filed on Jun. 30, 2000.

BACKGROUND OF THE INVENTION

[0002] The present invention relates to a process for preparing anocular lens with urethane compound and a process for preparing aurethane compound for medical instruments. More particularly, thepresent invention relates to a process for easily preparing a urethanecompound (macromonomer) showing high safety, which is very useful for amaterial of medical instruments represented by optical materials, forexample, an ocular lens such as a contact lens and an intraocular lens,artificial cornea, cornea onlay, cornea inlay. Furthermore, the presentinvention relates to a process for preparing a urethane compound whilemolecular weight of the compound is controlled.

[0003] At present, various urethane compounds such as urethane foam,urethane rubber, adhesives and polyurethane synthetic fiber areindustrially used. Urethane compounds are used for medical instrumentssuch as gloves, various kinds of tubes and catheters, and investigatedto be applied for an artificial cornea (Japanese Unexamined PatentPublication No. 325369/2000), an artificial heart, and the like.

[0004] In absence of a catalyst or in the presence of a compound such asan organic metal compound or a tertiary amine, hydroxyl group is reactedwith isocyanate group to form urethane bond. Particularly, from theviewpoint of high catalytic activity, the organic metal compounds aregenerally used. Among them, an organic tin compound is well known. Forexample, an ocular lens is reported which is made of a polyurethanecompound prepared by using an organic tin compound as a catalyst (U.S.Pat. No. 4,605,712 and the like).

[0005] However, it is considered that the organic tin compound which isgenerally known as a compound showing high toxicity must not be used asa catalyst for preparation of urethane materials when the urethanematerials are applied for medical instruments, such as an ocular lens,which are used in living organism or by contacting with living organism.The organic tin compound is recognized as a distraction substance forendocrine (environmental hormone) which is recently topical substance.Accordingly, some catalysts other than organic tin compounds areearnestly necessitated.

[0006] From the viewpoint of mechanical strength and excellent oxygenpermeability, urethane compounds containing siloxane structure have beenexamined for the use as medical instruments, in particular, opticalmaterials such as a contact lens material and an intraocular lensmaterial (Japanese Unexamined Patent Publication No. 22487/1979,Japanese Unexamined Patent Publication No. 121826/1994, U.S. Pat. Nos.5,451,617, 5,260,000, 5,760,100 and the like). However, because theurethane compounds disclosed in these references are prepared by usingthe organic tin compounds almost, these urethane compounds are notsuitable as medical materials on the basis of the above reasons. Even ifpurification of the urethane compound is carried out, the organic tincompounds remain within the urethane compound.

[0007] Usually, the above urethane compounds containing siloxanestructure (macromonomers) have been prepared by finally introducing apolymerizing group in a polyfunctional polysiloxane which is a mainchain through urethane bond (Japanese Unexamined Patent Publication No.179217/1986, Japanese Unexamined Patent Publication No. 35014/1991 andthe like). However, when this method is employed, it is inevitable thatthe polymerizing group is inestimably and repeatedly introduced in thepolyfunctional polysiloxane which is a main chain through urethane bond.As a result, molecular weight of the obtained urethane compound becomeshigher than planned molecular weight. Accordingly, there is a problemthat clear understanding for structure of the obtained compound isdifficult.

[0008] Because the above urethane compound containing siloxane structurebecomes high viscous solution according to its molecular weight or kindof reaction components, effective purification methods for the urethanecompound are not developed. So, it is very difficult to removeimpurities such as the above catalyst and by-products, and crudeurethane compound is used. Accordingly, the use of the urethanecompounds has been feared from the viewpoint of safety, including theabove problems.

[0009] Use of an amine catalyst instead of the organic tin compound forpreparing a urethane compound for a medical material is reported (U.S.Pat. No. 4,136,250). However, they are well known generally thatspecific amine catalysts have cytotoxicity (U.S. Pat. No. 5,955,560),and that amine catalysts are inferior to organic metal compounds incatalytic activity for reaction forming urethane bond and thereforerequiring a long time for preparing a urethane compound and increasing aformation ratio of by-products.

[0010] Therefore, various organic metal compounds have been investigatedas a reaction catalyst for forming urethane bond, because they have ahigh reaction activity for forming urethane bond, and a lowcytotoxicity.

[0011] For example, using an acetylacetonate salt of metal such as zinc,iron, or copper is reported for urethane reaction (U.S. Pat. No.4,879,032, Polymer preprints, Japan, 50, 1258, 2001). However, safetysuch as cytotoxicity is not evaluated. There are not disclosed effectssuch as reaction selectivity as a reaction catalyst for forming urethanebond by using a diisocyanate such as bifunctional compound.

[0012] When urethane materials are applied for medical materials, forexample, medical instruments such as an ocular lens used in a livingorganism or by contacting with a living organism, remaining of the abovementioned organic metal compound in a formed urethane compound is notpreferable even if the cytotoxicity is comparatively low. A method forremoving an organic metal compound from a formed urethane compound hasnot been reported in detail.

[0013] Since the above mentioned urethane compound may be formed as ahigh viscosity solution according to the molecular weight and kinds ofreaction substances, there is no effective purifying method. As aresult, it is very difficult to remove the above mentioned impuritiessuch as catalysts and by-products, and therefore the urethane compoundis used without purification, and there are problems in safety includingthe above-mentioned problem.

[0014] An object of the present invention is to provide a process foreasily preparing a urethane compound, in particular, while molecularweight of the compound is controlled, in the presence of a catalystshowing lower toxicity instead of the conventional organic tin compoundsand to provide a process for preparing an ocular lens with the urethanecompound.

[0015] This and other objects of the present invention will becomeapparent from the description hereinafter.

SUMMARY OF THE INVENTION

[0016] In accordance with the present invention, there is provided aprocess for preparing an ocular lens with a urethane compound comprisingthe steps of

[0017] a) preparing a urethane compound by reacting at least onehydroxyl compound and at least one isocyanate compound in the presenceof an organic iron compound,

[0018] b) removing the organic iron compound from the urethane compoundobtained in the step a)

[0019] c) mixing the urethane compound obtained in the step b) with atleast one compound selected from the group consisting of anothercopolymerizable compound, a crosslinking agent, a UV absorbent, a dye, apolymerization initiator, a photosensitizer, and an organic solvent toobtain a mixture, and

[0020] d) curing the mixture obtained in the step c) to prepare a lens.

[0021] In accordance with the present invention, there is also provideda process for preparing a urethane compound for medical instruments,characterized by reacting a hydroxyl compound with an isocyanatecompound in the presence of an organic iron compound represented by theformula (I)

[0022] in which each of R¹ and R² is independently selected from thegroup consisting of methyl group, trifluoromethyl group and phenylgroup, as a reaction catalyst to give a urethane compound.

[0023] According to the process of the present invention, a urethanecompound showing high safety, which is very useful for a material ofmedical instruments represented by optical materials, such as an ocularlens, can be easily prepared, in particular, while molecular weight ofthe compound is controlled.

DETAILED DESCRIPTION

[0024] One of the features of the present invention is that a reactionbetween a hydroxyl compound and an isocyanate compound is controlled byusing an organic iron compound. In a urethane reaction between hydroxylcompound having at least 2 functional groups and isocyanate compound atleast 2 functional groups, it is feared that chain is elongated bybonding repeatedly and the molecular weight of the urethane compound isincreased. Therefore, in the present invention, by using an organic ironcompound as a catalyst, reaction selectivity of an isocyanate compoundhaving at least 2 functional groups is increased SO that the molecularweight is prevented from increasing occurred as by-reaction. When aurethane compound is applied for medical materials, removing process ofa catalyst for urethane reaction is necessitated. Therefore, highextractivity of the catalyst from urethane compounds is important. As amethod for removing catalysts, generally, a method using organicsolvents is suitable, and therefore the solubility of the catalyst inorganic solvents is an important parameter. In the present invention, anorganic iron compound, which is high safety, has high reactivity, and isextracted easily, is used in a step for preparing a urethane compound byreacting at least one hydroxyl compound and at least one isocyanatecompound once or stepwise and repeatedly.

[0025] In the process for preparing a urethane compound for medicalinstruments, as mentioned above, the hydroxyl compound is reacted withthe isocyanate compound to give a urethane compound in the presence ofthe reaction catalyst other than the organic tin compound in order tomore accelerate this reaction.

[0026] In consideration of the use of the urethane compound as amaterial for medical instruments, particularly an ocular lens, as theabove reaction catalyst, an organic iron compound is used because ofexcellent safety.

[0027] Examples of the above organic iron compound are, for instance,iron diketonate such as iron (III) 2,4-pentandionate (acetylacetonate),iron(III) trifluoropentandionate, iron (III) benzoylacetonate, iron(III) hexafluoropentandionate, iron(III) dibenzoylpentandionate andiron(III) ethoxymethylpentandionate. As the above organic iron compoundis preferably represented by the formula (I).

[0028] In the formula (I), each of R¹ and R² is independently selectedfrom the group consisting of methyl group, trifluoromethyl group andphenyl group. Because molecular weight of the urethane compound can bemore sufficiently controlled, the organic iron compound is particularlypreferable.

[0029] In order to sufficiently exhibit acceleration effect for theprogress of reaction, it is desired that the amount of the reactioncatalyst is at least 10⁻⁶ mole, preferably at least 10⁻⁴ mole based on 1mole of the amount of hydroxyl group in the hydroxyl compound orisocyanate group in the isocyanate compound. In order to prevent removalof the reaction catalyst from being finally difficult after the finishof reaction, it is desired that the amount of the reaction catalyst isat most 10⁻¹ mole, preferably at most 10⁻² mole based on 1 mole of theamount of hydroxyl group in the hydroxyl compound or isocyanate group ofthe isocyanate compound. The amount of the reaction catalyst can besuitably adjusted within the above range according to kind of thehydroxyl compound and the isocyanate compound in urethane reactions asmentioned below.

[0030] In the present invention, the urethane reaction may be carriedout once or repeatedly in stepwise.

[0031] For example, a one-step reaction for preparing a urethanecompound is as follows. At least one member of dihydroxyl compounds asthe hydroxyl compound and at least one member of monoisocyanatecompounds as the isocyanate compound are used and reacted in the ratioof 1 mole of the dihydroxyl compound to 2 moles of the monoisocyanatecompound. As a result, two urethane bonds are formed.

[0032] In the present invention, it is possible that the below urethanecompound is prepared by, for instance, the following two-step urethanereactions (i) and (ii).

[0033] At first, in the urethane reaction (i), at least one member ofdihydroxyl compounds is used as the hydroxyl compound and at least onemember of diisocyanate compounds is used as the isocyanate compound, sothe dihydroxyl compound is reacted with the diisocyanate compound. As aresult, at least two urethane bonds are formed between hydroxyl group inthe dihydroxyl compound and isocyanate group in the diisocyanatecompound.

[0034] When 1 mole of the dihydroxyl compound is reacted with 2 moles ofthe diisocyanate compound, two urethane bonds are formed and a compoundhaving isocyanate groups in its both ends respectively through twourethane bonds is synthesized. On the other hand, when 2 moles of thedihydroxyl compound is reacted with 1 mole of the diisocyanate compound,two urethane bonds are formed and a compound having hydroxyl groups inits both ends respectively through two urethane bonds is synthesized.

[0035] In the urethane reaction (i), the dihydroxyl compound is notlimited to one member and the diisocyanate compound is also not limitedto one member. So, at least two members of each compound can be usedwith suitable combination. Accordingly, in a compound synthesized in theurethane reaction (i), units derived from at least two members of thedihydroxyl compounds and/or units derived from at least two members ofthe diisocyanate compounds can be included.

[0036] Then, in the urethane reaction (ii),

[0037] (a) the compound having isocyanate groups in its both endsobtained in the above urethane reaction (i) is reacted with at least onemember of monohydroxyl compounds as the hydroxyl compound, for example,in the ratio of 2 moles of the monohydroxyl compound based on 1 mole ofthe compound having isocyanate groups in its both ends obtained in theabove urethane reaction (i) to form urethane bond; or

[0038] (b) the compound having hydroxyl groups in its both ends obtainedin the above urethane reaction (i) is reacted with at least one memberof monoisocyanate compounds as the isocyanate compound, for example, inthe ratio of 2 moles of the monoisocyanate compound based on 1 mole ofthe compound having hydroxyl groups in its both ends obtained in theabove urethane reaction (i) to form urethane bond. By each reaction, theurethane compound having at least four urethane bonds is prepared.

[0039] Because molecular weight of the aimed urethane compound can becontrolled and structure of this compound can be exactly clarified, itis desired that the above two-step urethane reactions (i) and (ii) arecarried out in the present invention.

[0040] For example, a three-step reaction for preparing a urethanecompound is as follows. At least one member of dihydroxyl compounds asthe hydroxyl compound and at least one member of diisocyanate compoundsas the isocyanate compound are used and reacted, for example, in theratio of 1 mole of the dihydroxyl compound to 2 moles of thediisocyanate compound. As a result, two urethane bonds are formedbetween each of two hydroxyl groups in the dihydroxyl compound and oneisocyanate group of each of two diisocyanate compounds to produce acompound having isocyanate groups in its both ends through two urethanebonds. Then, at least one member of dihydroxyl compounds same with ordifferent from that used in the prior step as a hydroxyl compound in theratio of 2 moles to form four urethane bonds in total producing acompound having hydroxyl groups in its both ends. Further, at least onemember of monoisocyanate compounds is reacted as an isocyanate compoundin the ratio of 2 moles to produce a urethane compound in which sixurethane bonds are formed in total.

[0041] In the present invention, at least one of the hydroxyl compoundor at least one of the isocyanate compound preferably has apolydimethylsiloxane structure having a repetition number of 1 to 1500from the viewpoint of flexibility and excellent oxygen permeability.

[0042] In the present invention, at least one of the hydroxyl compoundor at least one of the isocyanate compound preferably has aperfluoropolyether structure having a repetition number of 1 to 1500from the viewpoint of flexibility and anti-fouling.

[0043] In the present invention, at least one of the hydroxyl compoundor at least one of the isocyanate compound preferably has a hydrophilicpolymer structure having a molecular weight of 100 to 1000000 from theviewpoint of hydrophilicity or water-absorption.

[0044] Examples of dihydroxyl compound, monohydroxyl compound,diisocyanate compound, and monoisocyanate compound are as follows.

[0045] Typical examples of the dihydroxyl compound are, for instance, ahydroxyl group-containing polysiloxane compound represented by theformula (II):

[0046] wherein each of R¹ and R² is independently an alkylene grouphaving 1 to 20 carbon atoms, or phenyl, —X— is oxygen, S, direct bond,each of R³, R⁴, R⁵, R⁶, R⁷ and R⁸ is independently a linear alkyl grouphaving 1 to 20 carbon atoms, or hydrogena branched alkyl group having 3to 20 carbon atoms or a cyclic alkyl group having 3 to 20 carbon atoms,which may be substituted with fluorine atom, x is an integer of 1 to1500, y is an integer of 1 to 1499, and “x+y” is an integer of 1 to1500; and the like.

[0047] In the above formula (II), each of R¹ and R² is preferably analkylene group having 1 to 10 carbon atoms. Each of R³, R⁴, R⁵, R⁶, R⁷and R⁸ is preferably a linear alkyl group which may be substituted withfluorine atom, having 1 to 5 carbon atoms, a branched alkyl group whichmay be substituted with fluorine atom, having 3 to 5 carbon atoms, or acyclic alkyl group which may be substituted with fluorine atom, having 3to 5 carbon atoms. Also, x is preferably an integer of 1 to 500, y ispreferably an integer of 1 to 499, and “x+y” is preferably an integer of1 to 500.

[0048] The other concrete examples of a dihydroxyl compound are, forinstance, α,ω-dihydroxyl alkyl perfluoro polyether, polyethylene glycol,polypropylene glycol. Concrete examples of the polyfunctional hydroxylcompound containing hydrophilic polymer structure are poly(vinylalcohol), poly(2-hydroxyl ethyl (meth)acrylate); as well as a polymermade by inserting a compound having hydroxyl group at polymerization,for example, vinylpyrrolidone (NVP), (meth)acrylic acid, (meth)acrylicacid salt, or a cyclic ether such as a tetrahydrofuran, oxetanederivative; a lactone, lactam such as ε-caprolactone, or ε-caprolactam;a cyclic imino ether such as an oxazoline derivative;dimethylacrylamide, diethylacrylamide; a monomer containing zwitterionicgroup such as 2-methacryloyloxyethylphosphorylcholine. Thepolymerization process is not limited. For example, the polymer may beprepared by radical copolymerization with a monomer containing hydroxylgroup, or by transforming the end groups to hydroxyl group after ionicpolymerization.

[0049] Because the molecular weight of the polymer or oligomer segmentin a hydroxyl compound influences molecular weight of a final product,the molecular weight is desired to be 100 to 1000000, preferably 100 to1000000. When the molecular weight is lower than 100, the final productis decreased in molecular weight to become insufficient in mechanicalstrength, hardness and the like as a polymer. When the molecular weightis higher than 1000000, the final product is excessively increased inmolecular weight to become insufficient in mechanical strength, hardnessand the like as a polymer.

[0050] Typical examples of the diisocyanate compound are, for instance,a diisocyanate compound represented by the formula (III):

O═C═N—R¹⁰—N═C═O  (III)

[0051] wherein R¹⁰ is a linear aliphatic hydrocarbon group having 1 to20 carbon atoms, a branched hydrocarbon group having 2 to 20 carbonatoms, a cyclic aliphatic hydrocarbon group having 3 to 20 carbon atomsor an aromatic hydrocarbon group having 6 to 20 carbon atoms; and thelike.

[0052] Concrete examples of the isocyanate compound are, for instance,ethylenediisocyanate, isophoronediisocyanate (IPDI),1,6-hexamethylenediisocyanate, 1,2-toluenediisocyanate,1,4-toluenediisocyanate, diisocyanate, bis(2-isocyanatethyl) fumarate,1,5-naphthalenediisocyanate, cyclohexyl-1,4-diisocyanate,4,4′-dicyclohexylmethanediisocyanate (HMDI),diphenylmethane-4,4′-diisocyanate,2,2,4-(2,4,4)-trimethylhexane-1,6-diisocyanate and the like.

[0053] Typical examples of the monohydroxyl compound are, for instance,a compound having hydroxyl group and an active unsaturated group, suchas a hydroxyalkyl (meth)acrylate, allyl alcohol, vinylbenzyl alcohol,monohydroxyl fumarate, monohydroxyl maleate or monohydroxyl itaconate;and the like.

[0054] In consideration of copolymerizability of the aimed urethanecompound with the other copolymerizable compound having an activeunsaturated group, among the above exemplified compounds, a hydroxyalkyl(meth)acrylate is preferable. Concrete examples of the hydroxyalkyl(meth)acrylate are, for instance, 2-hydroxyethyl (meth)acrylate,2-hydroxypropyl (meth)acrylate, 3-hydroxypropyl (meth)acrylate,4-hydroxybutyl (meth)acrylate. For instance, diethylene glycolmono(meth)acrylate, triethylene glycol mono(meth)acrylate, allylalcohol, ethylene glycol allyl ether, diethylene glycol allyl ether,glycidol, an epoxide drivative having hydroxyl group, an oxetanederivative having hydroxyl group, an oxazoline derivative havinghydroxyl group, and the like.

[0055] Typical examples of the monoisocyanate compound are, forinstance, a compound having isocyanate group and an active unsaturatedgroup, such as allylisocyanate, vinylisocyanate, vinylbenzylisocyanateor 2-isocyanatethyl (meth)acrylate; and the like.

[0056] When, for example, the above reaction (b) in the urethanereaction (ii) is carried out, because the number of urethane bond in theurethane compound can be controlled and mechanical strength can beimparted to the urethane compound, it is desired that a compoundcontaining a monoisocyanate compound prepared by reacting thediisocyanate compound with the monohydroxyl compound is used as themonoisocyanate compound. It is particularly desired that only themonoisocyanate compound is used as the monoisocyanate compound.

[0057] It is considered that the ratio of the dihydroxyl compound to thediisocyanate compound in the urethane reaction (i) considerably effectsfor the amount of prepared by-products, the amount of residualnon-reacted compounds, and molecular weight and molecular weightdistribution of the aimed urethane compound.

[0058] In the above-mentioned urethane reaction, from the viewpoint ofreduction of residual non-reacted isocyanate groups, it is desired thatthe total amount of hydroxyl group in the dihydroxyl compound based on 1mole of isocyanate group in the diisocyanate compound is at least 0.4mole, preferably at least 0.5 mole, more preferably at least 0.6 mole,particularly preferably at least 0.7 mole, more particularly preferablyat least 0.8 mole. From the viewpoint of reduction of residualnon-reacted dihydroxyl compound which not bonds to the isocyanatecompound through urethane bond, it is desired that the total amount ofhydroxyl group in the dihydroxyl compound based on 1 mole of isocyanategroup in the diisocyanate compound is at most 2 moles, preferably atmost 1.5 moles, more preferably at most 1.35 moles, particularlypreferably at most 1.25 moles.

[0059] The amount of the dihydroxyl compound and the diisocyanatecompound is adjusted within the above range. Then, these compounds arereacted by stirring and mixing with each other.

[0060] In the above reaction (a), the monohydroxyl compound to bereacted with the compound having isocyanate groups in its both ends isnot limited to one member. At least two members of the monohydroxylcompounds can be suitably used. In the above reaction (b), themonoisocyanate compound to be reacted with the compound having hydroxylgroups in its both ends is not limited to one member. At least twomembers of the monoisocyanate compounds can be suitably used. As aresult, the urethane compound obtained in the reaction (a) or (b) cancontain the unit derived from two members of the monohydroxyl compoundsor the unit derived from two members of the monoisocyanate compounds.

[0061] In accordance that the above urethane reaction (i) is finishedonly one time or repeatedly carried out stepwise, the number of urethanebond and the number of unit (block) derived from each component in theurethane compound synthesized in the urethane reaction (ii) vary. As aresult, for instance, a diblock-type urethane compound is synthesized.Because chain length of each segment in the diblock-type urethanecompound is controlled, various different effects can be exhibited.

[0062] In the above reaction, reaction time is not particularly limitedand suitably adjusted according to kind and combination of eachcompound. In order to prevent insufficient reaction, it is desired thatreaction time is at least 1 minute, preferably at least 30 minutes. Inorder to prevent polymerization due to polymerizable compounds duringreaction, it is desired that reaction time is at most 100 hours,preferably at most 50 hours.

[0063] In the above reaction, reaction temperature is not particularlylimited and suitably adjusted according to kind and combination of eachcompound. In order to prevent insufficient reaction, it is desired thatreaction temperature is at least −30° C., preferably at least 0° C., andmore preferably at least 30° C. In order to prevent polymerization dueto polymerizable compounds during reaction, it is desired that reactiontemperature is at most 150° C., preferably at most 100° C. In thereaction, each of the reaction temperature in reaction steps can bedifferent from each other.

[0064] The hydroxyl compound can be reacted with the isocyanate compoundin the absence of a solvent or in the presence of an organic solvent.

[0065] Examples of the organic solvent are, for instance, acetone,n-hexane, tetrahydrofuran, benzene, toluene, acetonitrile, methylenechloride and the like.

[0066] When the organic solvent is used, in order to remove the fearthat it becomes difficult to react the hydroxyl compound with theisocyanate compound, and so, the yield of the urethane compound islowered, it is desired that the total concentration of the hydroxylcompound and the isocyanate compound in the organic solvent is at least0.01 mol/L, preferably at least 0.1 mol/L. That is, the amount (volume)of the organic solvent can be calculated according to the totalconcentration of the hydroxyl compound and the isocyanate compound. Areaction solution composed of the hydroxyl compound, the isocyanatecompound and the organic solvent is sufficiently stirred or shaken sothat the reaction uniformly proceeds. In the reaction, the solvent canbe presence or absence in each of reaction steps independently.

[0067] In accordance with the above steps, the aimed urethane compoundcan be prepared. After finishing the reaction for preparing the urethanecompound, it is desired that the urethane compound is purified byremoving non-reacted compounds, compounds having lower molecular weight(by-products) and catalysts.

[0068] For purification of the urethane compound, an organic solvent ispreferably used. In addition, the urethane compound can be purified byusing a supercritical fluid with referring to “Polymer Applications,Vol. 43, No. 11, p. 38 (1994)”.

[0069] As the above organic solvent for purification, a solvent whichcan dissolve the non-reacted compounds, by-products and catalysts or candissolve the urethane compound is used. Typical examples of the organicsolvent are, for instance, methanol, ethanol, acetone, tetrahydrofuran,acetonitrile, methylene chloride, hexane and the like. These can be usedalone or in admixture thereof. In order to more effectively purify theurethane compound, methanol, acetonitrile and methylene chloride, amixed solvent of hexane and methanol and a mixed solvent of hexane andacetonitrile are preferably used.

[0070] An organic solvent, which dissolves an organic iron compound, isdesired for removing effectively the organic iron compound as acatalyst. There are more large kinds of organic solvents, whichdissolves an organic iron compound (iron diketonate) used in the presentinvention, than organic solvents, which dissolves other metaldiketonates. An organic iron compound is soluble more easily than theother organic metal compounds. For removing an organic iron compoundfrom the urethane compound, it is effective that the organic ironcompound is more easily extracted.

[0071] In order to sufficiently remove the non-reacted compounds,by-products and catalysts, it is desired that the amount of the organicsolvent is, on the basis of the volume, at least {fraction (1/20)} time,preferably at least {fraction (1/10)} time of the amount of the urethanecompound. In order to prevent the amount of waste fluid from increasingafter purification, it is desired that the amount of the organic solventis, on the basis of the volume, at most 20 times, preferably at most 10times, and more preferably at most 5 times of the amount of the urethanecompound.

[0072] As the above supercritical fluid for purification, a fluid in thesupercritical state, such as water, carbon dioxide, methanol, ethane orpropane may be cited. Carbon dioxide is preferable among them, becausethe extraction can be carried out at around a normal temperature due toits critical temperature of about 31° C., because quality of the extractchanges in low degree by chemical change due to its inactivity inpractical use, because the residual amount in the extract is low due toits gas state under the atmospheric pressure, because it is safety gasdue to no toxicity and nonflammability, and because it can be suppliedin large amount due to low cost.

[0073] An extraction with supercritical fluid comprising a stepextracting a catalyst and a lower molecular weight compound from aurethane compound and a step separating the urethane compound from thesolvent (the supercritical fluid). For example, in removing by apressure swing method, the supercritical fluid is transferred by a pumpfrom a storage to an extractor through one heat exchanger to compressthe fluid to an extraction pressure and another heat exchanger to adjustthe temperature of the fluid to an extraction temperature. In theprocess, the supercritical fluid contacted with an urethane compound inthe extractor and containing a catalyst and a low molecular weightcompound is decompressed and transferred to a separator through a heatexchanger, and the catalyst and the lower molecular weight compound areseparated from the supercritical fluid. The supercritical fluid flowingout from the separator in gas state is purified with filter, and reused.

[0074] Condition as to purification with the supercritical fluid variesaccording to molecular weight and chemical structure of the urethanecompound. So, the condition cannot be sweepingly determined. Forinstance, it is desired that treating pressure is 5 to 100 MPa, andtreating temperature is 0° to 100° C.

[0075] In order to more effectively extract the compounds having lowermolecular weight, an auxiliary for extraction can be used duringpurification of the urethane compound with the supercritical fluid.Examples of the auxiliary for extraction are, for instance,acetonitrile, methanol and the like.

[0076] The urethane compound produced in the present invention may havean ethylenic unsaturated group capable of radical polymerization or afunctional group capable of photo cationic crosslinking. The ethylenicunsaturated group capable of radical polymerization may be, for example,a group derived from (meth)acrylate group, allyl group, or vinyl group.The functional group capable of photo cationic crosslinking may be, forexample, a cyclic ether derivative such as epoxide, oxetane, orcyclohexene oxide; a cyclic sulfide derivative; a cyclic iminoetherderivative such as oxazoline. The introducing method for an ethylenicunsaturated group capable of radical polymerization or a functionalgroup capable of photo cationic crosslinking into a urethane compound isnot limited. For example, a hydroxyl compound derivative or isocyanatecompound derivative having at least one of these groups can be used.These groups can be introduced into a urethane compound at a residualreactive group of the urethane compound by a post-treatment. As anexample of introduction by a post-treatment, when polysiloxane diolhaving hydrosilane group is selected as dihydroxyl group, thesefunctional group can be easily introduced into polysiloxane diol byhydro-silylation with allyl oxetane and the like in the presence of aplatinum catalyst.

[0077] The introducing ratio of the functional group is not particularlylimited, but the ratio is desirably adjusted because the ratioinfluences properties of an ocular lens made by using the urethanecompound, particularly mechanical property.

[0078] When the urethane compound is prepared by the urethane reaction(i) or (ii), in order to prevent active unsaturated groups in eachcompound from polymerizing with each other, it is desired that apolymerization inhibitor is suitably used.

[0079] Examples of the polymerization inhibitor are, for instance, astable radical compound; an addition inhibitor such as oxygen, abenzoquinone derivative or a nitro compound; and the like. Hydroquinone,hydroquinone methyl ether, p-methoxyphenol and butylhydroxytoluene arepreferably exemplified. It is desired that the amount of thepolymerization inhibitor based on 100 parts by weight (hereinafterreferred to as “part(s)”) of all the compounds having an activeunsaturated group is about 0.01 to 1 part.

[0080] In the present invention, an ocular lens can be obtained bycuring a mixture of a urethane compound having the above-mentionedethylenic unsaturated group capable of radical polymerization orfunctional group capable of photo cationic crosslinking, and at leastone compound selected from the group consisting of anothercopolymerizable monomer, a crosslinking agent, a UV absorbent, a dye, apolymerization initiator, a photo sensitizer and an organic solvent toproduce a lens.

[0081] The copolymerizable monomer, crosslinking agent, UV absorber,dye, polymerization initiator, photo sensitizer, and organic solvent arenot particularly limited, and can be selected preferably according todesired properties of the ocular lens.

[0082] For example, the compound described in Japanese PatentPublication No.2774233, WO 01/71415, or Japanese Examined PatentPublication No. 55122/1987 can be used. As a hydrophilic monomer,acryloyl morpholine, and N-methyl-3-methylene-2-pyrrolidone can be used.

[0083] The curing method for the above-mentioned mixture is notparticularly limited. The mixture can be cured by adding a thermalpolymerization initiator for thermal curing, or by adding a photoinitiator and a photo sensitizer for photo curing. Curing with electronbeam can be cited by selecting the acrylic group as ethylenicunsaturated group.

[0084] An ocular lens material obtained in such a manner can be used fora hard lens, a soft lens containing water or an intraocular lens,artificial cornea, cornea onlay, cornea inlay, and is not particularlylimited in its shape.

[0085] The obtained ocular lens can be subjected to a surfacemodification, for example, plasma treatment (with oxygen, nitrogen,argon, helium and the like or mixtures thereof), UV irradiation, ExcimerUV irradiation, plasma polymerization (with a mixture of methane/air andthe like), graft polymeration with a hydrophilic monomer such as DMA,NVP or PEG.

[0086] According to the process of the present invention, the urethanecompound showing high safety, which is very useful for a material ofmedical instruments represented by optical materials such as an ocularlens can be easily prepared, in particular, while molecular weight ofthe compound is controlled.

[0087] The process for preparing a urethane compound for medicalinstruments or an ocular lens of the present invention is morespecifically described and explained by means of the following Examples.It is to be understood that the present invention is not limited to theExamples, and various changes and modifications may be made in theinvention without departing from the spirit and scope thereof.

[0088] <Catalytic Reactivity>

EXAMPLE A1 FeAA

[0089] A 100 mL three-necked flask having a side tube equipped withDimroth reflux condenser, a mechanical stirrer and a thermometer waspreviously substituted with nitrogen gas and charged with 15.50 g (100mmole) of IEM and 0.035 g (0.1 mmole) of FeAA. Then, the flask wascharged with 5.40 g (100 mmole) of 1-butanol and stirred at 23° C. Apart of the obtained reaction mixture was sampled after one hour todetect given products with GC/MS analysis. Conversion rate of IEM wasestimated from the proportion of the products. The result is shown inTABLE 1.

[0090]¹H-NMR analysis, FT/IR analysis, SEC analysis, evaluation oftransparency and cytotoxicity test were carried out in accordance withthe following methods, respectively.

[0091] (I) ¹H-NMR Analysis

[0092]¹H-NMR spectrum was examined under the following conditions.

[0093] Fourier transform NMR spectrometer: GEMINI2000/400BB type, madeby Varian Technologies Limited

[0094] Nuclear: ¹H (resonance frequency: 400.42 MHz)

[0095] Solvent: CDCl₃

[0096] Test sample: About 5 to 10 w/v % CDCl₃ solution

[0097] Measuring temperature: About 22° C.

[0098] (II) FT/IR Analysis

[0099] FT/IR spectrum was examined under the following conditions.

[0100] Infrared spectrophotometer: FT/IR-8300, made by Nippon Bunko

[0101] Kabushiki Kaisha

[0102] Method: KBr disk method

[0103] (III) SEC Analysis

[0104] SEC analysis was carried out under the following conditions.

[0105] SEC system: Made by Nippon Bunko Kabushiki Kaisha

[0106] Column oven: 860-CO made by Nippon Bunko Kabushiki Kaisha

[0107] Degasser: DG-980-50 made by Nippon Bunko Kabushiki Kaisha

[0108] Pump: PU-980 made by Nippon Bunko Kabushiki Kaisha

[0109] Detector (RI type): 830-RI made by Nippon Bunko Kabushiki Kaisha

[0110] (UV type): SPD-10A made by SHIMAZU CORPORATION

[0111] Column: Ultrastyragel Plus MX 10³ Å made by Waters Co. (twocolumns connected in series)

[0112] Eluent: Tetrahydrofuran

[0113] Calibration curve: Produced by using standard polystyrene

[0114] (IV) Evaluation of Transparency

[0115] The test sample was observed with naked eye.

[0116] (V) Cellular Toxicity Test (Test as to Prevention for Preparationof Colony)

[0117] The test was carried out in accordance with the guideline of“Basic biological test of medical instruments and medical materials”(MEDICAL DEVICES DIVISION PHARMACEUTICAL AFFAIRS BUREAU Notification No.99, 1995, published on Jun. 27, 1995 in Japan). Then, biological safetyof the test sample was evaluated.

EXAMPLE A2 FeTFPD

[0118] The same procedure of Example A1 was carried out except that0.052 g (0.1 mmole) of Iron (III) trifluoropentandionate (FeTFPD) wasused instead of 0.035 g (0.1 mmole) of FeAA. The result is shown inTABLE 1.

EXAMPLE A3 FeBzAc

[0119] The same procedure of Example A1 was carried out except that0.055 g (0.1 mmole) of Iron (III) benzoylacetonate (FeBzAc) was usedinstead of 0.035 g (0.1 mmole) of FeAA. The result is shown in TABLE 1.

COMPARATIVE EXAMPLE A1 ZnAA

[0120] The same procedure of Example A1 was carried out except that0.026 g (0.1 mmole) of Zinc acetylacetonate (ZnAA) was used instead of0.035 g (0.1 mmole) of FeAA. The result is shown in TABLE 1.

COMPARATIVE EXAMPLE A2 CuAA

[0121] The same procedure of Example A1 was carried out except that0.026 g (0.1 mmole) of Copper acetylacetonate (CuAA) was used instead of0.035 g (0.1 mmole) of FeAA. The result is shown in TABLE 1. TABLE 1 No.Catalyst Conversion rate of IEM (%) Ex. A1 FeAA 78 Ex. A2 FeTFPD 77 Ex.A3 FeBzAc 74 Com. Ex. A1 ZnAA 65 Com. Ex. A2 CuAA 37

[0122] <Catalytic Reactivity and Selectivity>

EXAMPLE A4 FeAA

[0123] A 100 mL three-necked flask having a side tube equipped withDimroth reflux condenser, a mechanical stirrer and a thermometer waspreviously substituted with nitrogen gas and charged with 22.21 g (100mmole) of IPDI and 0.035 g (0.1 mmole) of FeAA. Then, the flask wascharged with 11.60 g (100 mmole) of HEA and stirred at 23° C. A part ofthe obtained reaction mixture was sampled after three hours to detectgiven products with GC/MS analysis. Conversion rate of IPDI andselectivity were estimated from the proportion of the products. Theresults are shown in TABLE 2.

[0124] The reaction carried out in this Example is shown in thefollowing Scheme 1. In Scheme 1, k1, k2, k3 and k4 indicate a reactionvelocity constant of each reactions respectively.

[0125] A monourethane given by urethane reaction of primary isocyanategroup of IPDI (prim.-mono urethane: p-mU) and a monourethane given byurethane reaction of secondary isocyanate group of IPDI (sec.-monourethane: s-mU) were isolated by GC. These monourethanes were detectedas trans-form and cis-form respectively. T (=k1/k2) indicatingselectivity was estimated from the ratio of GC area of each products.

[0126] When T is equal to 1, reactivity of primary isocyanate group (k2)is equal to that of secondary isocyanate group (k1) giving a largeamount of by-products having a high molecular weight. When T is muchlarger than 1, reactivity of primary isocyanate group (k2) is muchsmaller than that of secondary isocyanate group (k1) giving a smallamount of by-products having a high molecular weight.

EXAMPLE A5 FeDBzPD

[0127] The same procedure of Example A4 was carried out except that0.061 g (0.1 mmole) of FeDBzPD was used instead of FeAA. The result isshown in TABLE 2.

EXAMPLE A6 AlAA

[0128] The same procedure of Example A4 was carried out except that0.055 g (0.1 mmole) of AlAA was used instead of FeAA. The result isshown in TABLE 2.

COMPARATIVE EXAMPLE A3 ZnAA

[0129] The same procedure of Example A4 was carried out except that0.026 g (0.1 mmole) of ZnAA was used instead of FeAA. The result isshown in TABLE 2.

COMPARATIVE EXAMPLE A4 CuAA

[0130] The same procedure of Example A4 was carried out except that0.026 g (0.1 mmole) of CuAA was used instead of FeAA. The result isshown in TABLE 2.

COMPARATIVE EXAMPLE A5 Manganese (III) Acetylacetonate: MnAA

[0131] The same procedure of Example A4 was carried out except that0.025 g (0.1 mmole) of MnAA was used instead of FeAA. The result isshown in TABLE 2.

COMPARATIVE EXAMPLE A6 Aluminium (III) Acetylacetonate: AlAA

[0132] The same procedure of Example A4 was carried out except that0.032 g (0.1 mmole) of AlAA was used instead of FeAA. The result isshown in TABLE 2.

COMPARATIVE EXAMPLE A7 BSnL

[0133] The same procedure of Example A4 was carried out except that0.063 g (0.1 mmole) of BSnL was used instead of FeAA. The result isshown in TABLE 2. TABLE 2 Conversion rate Selectivity No. Catalyst ofIPDI (%) s-mU/p-mU Ex. A4 FeAA 77 4.0 Ex. A5 FeDBzPD 75 3.8 Ex. A6FeBzAc 75 3.7 Com. Ex. 3 ZnAA 60 2.5 Com. Ex. 4 CuAA 35 2.8 Com. Ex. 5MnAA 82 1.7 Com. Ex. 6 AlAA 24 1.4 Com. Ex. 7 BSnL 73 5.8

EXAMPLE A7 FeAA

[0134] A 100 mL three-necked flask having a side tube equipped withDimroth reflux condenser, a mechanical stirrer and a thermometer waspreviously substituted with nitrogen gas and charged with 26.25 g (100mmole) of HMDI and 0.035 g (0.1 mmole) of FeAA. Then, the flask wascharged with 11.60 g (100 mmole) of HEA and stirred at 23° C.

[0135] A part of the obtained reaction mixture was sampled after threehours to detect given products with GC/MS analysis. Conversion rate ofHMDI was estimated from the proportion of the products. Selectivity wasestimated from the molar ratio of mono-adduct to diadduct (mono-U/di-U).The result is shown in TABLE 3.

COMPARATIVE EXAMPLE A8 ZnAA

[0136] The same procedure of Example A7 was carried out except that0.026 g (0.1 mmole) of ZnAA was used instead of 0.035 g (0.1 mmole) ofFeAA. The result is shown in TABLE 3.

COMPARATIVE EXAMPLE A9 CuAA

[0137] The same procedure of Example A7 was carried out except that0.026 g (0.1 mmole) of CuAA was used instead of FeAA. The result isshown in TABLE 3. TABLE 3 Conversion rate Selectivity No. Catalyst ofHMDI (%) mono-U/di-U Ex. 3 FeAA 74 2.6 Com. Ex. 8 ZnAA 62 1.9 Com. Ex. 9CuAA 38 2.3

[0138] The results in TABLE 1 indicate that an organic iron catalyst(FeAA) has the highest activity to reaction of an isocyanate compoundhaving one functional group with a hydroxyl compound.

[0139] The results in TABLES 2 and 3 indicate that only Iron diketonateis effective for increasing selectivity in reaction of IPDI and HMDI.Among various organic metal catalysts, especially metal acetylacetonatecomplexes, only Iron diketonate such as a FeAA provides a highselectivity in reaction of IPDI and HMDI.

[0140] <Solubility of Catalysts>

[0141] Solubility of a various kind of catalysts in a various kind ofsolvents (water, methanol, acetone, acetonitrile, n-hexane, methylenechloride) was evaluated by studying maximum amount of catalystscompletely soluble in a various kind of solvents. TABLE 4 Solubility(mg/mL) methylene Catalyst water methanol acetone acetonitrile n-hexanechloride FeAA 1 50 25 50  1 50 ZnAA insoluble 50  1 insoluble insoluble10 CuAA insoluble insoluble  1 insoluble insoluble 10 MnAA insoluble 10 1 insoluble insoluble  1 AlAA insoluble 50 50 50 insoluble 50 BSnLinsoluble 50 50 50 50 50

[0142] The results in TABLE 4 show that FeAA has high solubility tovarious organic solvents compared with other catalysts. In addition,FEAA dissolves slightly in water. FeAA is removed by using water as wellas using a various kind of organic solvents.

[0143] <Residual Catalyst>

EXAMPLE B1 FeAA

[0144] A one-litter three-necked flask having a side tube equipped withDimroth reflux condenser, a mechanical stirrer and a thermometer waspreviously substituted with nitrogen gas and charged with 280.80 g ofpolydimethylsiloxane containing hydroxyl groups in its both ends(polymerization degree: 40, Hydroxyl group equivalent: 1560 g/molesupplied by Aldrich, code name: KF-6002, made by Shin-Etsu Chemical Co.,Ltd.; hereinafter referred to as “DHDMSi-40”). Then, the flask wascharged with 1 mL of an acetonitrile solution in which 0.12 g of FeAAwas previously dissolved, and then heated in an oil bath at 80° C. andstirred. Then the flask was charged with 62.0 g (0.40 mole) of2-isocyanatoethylmethacrylate (IEM) and stirred for 4 hours until thepeak at about 2230 cm⁻¹ indicating isocyanate group was disappeared inFT/IR analysis. A part of the reaction mixture was sampled forstructural analysis to detect formation of an intermediate product with¹H-NMR and FT/IR.

[0145]¹H-NMR (in CDCl₃); δ0.06 (Si—CH₃, m), 0.52 (Si—CH₂, 2H, m), 1.94(—CH₃, 3H, s), 2.91 (NH—CH₂, 2H, d), 3.02 (CH₂—N═C═O, 2H, s), 3.42(—O—CH₂, 2H, t), 3.61 (—O—CH₂, 2H, m), 4.85 (NH, 1H, s), 5.59(CH═, 1H,s), 6.12 (CH═, 1H, s)

[0146] FT/IR: 1630 (C═C), 1262 and 802 cm⁻¹ (Si—CH₃), 1094 and 1023(Si—O—Si), adjacent to 1728 (C═O and ester, urethane)

[0147] A crude urethane product obtained as above and dissolved in 2 Lof n-hexane was transferred to 5 L separatory funnel having a side tube.Then, the separatory funnel was charged with 500 mL of acetonitrile,stirred for 10 min at about 500 rpm, and then left to stand. Theacetonitrile phase was removed. The washing with acetonitrile wascarried out. The n-hexane phase was recovered and organic solvents andlower molecular weight compounds were stripped under reduced pressure. Apurified urethane compound of 294.80 g was obtained (Yield 86%).

[0148] The amounts of residual iron catalyst in the purified compoundwere detected by absorptiometry. The safety was evaluated bycytotoxicity test (colony assay). The molecular weight was measured andlower molecular weight compounds were detected by SEC. The results areshown in TABLES 5, and 6.

EXAMPLE B2 FeDBzPD

[0149] The same procedure of Example B1 was carried out except that 0.20g of FeDBzPD was used instead of FeAA. The result is shown in TABLES 5,and 6.

EXAMPLE B3 FeAA

[0150] A one-litter three-necked flask having a side tube equipped withDimroth reflux condenser, a mechanical stirrer and a thermometer waspreviously substituted with nitrogen gas and charged with 75.48 g (0.34mmole) of IPDI and 0.12 g of FeAA. Then, the flask was charged with529.90 g of DHDMSi-40, heated in an oil bath at 80° C., and stirred forabout 4 hours. A part of the reaction mixture was sampled for structuralanalysis to detect formation of an intermediate product with ¹H-NMR andFT/IR.

[0151]¹H-NMR (in CDCl₃); δ0.06 (Si—CH₃, m), 0.52 (Si—CH₂, 2H, m), 2.91(NH—CH₂, 2H, d), 3.02 (CH₂—N═C═O, 2H, s), 3.42 (—O—CH₂, 2H, t), 3.61(—O—CH₂, 2H, m), 4.54 (NH, 1H, s), 4.85 (NH, 1H, s)

[0152] FT/IR: 1262 and 802 cm⁻¹ (Si—CH₃), 1094 and 1023 (Si—O—Si),adjacent to 1728 (C═O, urethane), 2227 (N═C═O)

[0153] Then, the flask was charged with 39.47 g (0.34 mole) of HEA and0.20 g of p-methoxyphenol (MEHQ) as a polymerization inhibitor, andstirred in an oil bath at 80° C. After about three hours, formation of aurethane compound was detected with ¹H-NMR and FT/IR.

[0154]¹H-NMR (in CDCl₃); δ0.06 (Si—CH₃, m), 0.52 (Si—CH₂, 2H, m), 2.91(NH—CH₂, 2H, d), 3.02 (CH₂—N═C═O, 2H, s), 3.42 (—O—CH₂, 2H, t), 3.61(—O—CH₂, 2H, m), 4.18-4.34 (—(O)CO—CH₂—, 6H, m), 4.54 (NH, 1H, s), 4.85(NH, 1H, s), 5.84 (CH═, 1H, dd), 6.14 (CH═, 1H, dd), 6.43 (CH═, 1H, dd)

[0155] FT/IR: 1262 and 802 cm⁻¹ (Si—CH₃), 1094 and 1023 (Si—O—Si), 1632(C═C), adjacent to 1728 (C═O, ester and urethane)

[0156] A crude urethane compound obtained as above and dissolved in 2 Lof n-hexane was transferred to 5 L separatory funnel having a side tube.Then, the separatory funnel was charged with 500 mL of acetonitrile,stirred for 10 min at about 500 rpm, and then left to stand. Theacetonitrile phase was removed. The washing with acetonitrile wascarried out twice. The n-hexane phase was recovered and organic solventsand lower molecular weight compounds were stripped under reducedpressure. A purified urethane compound of 522.33 g was obtained (Yield81%).

[0157] When methanol was used instead of above acetonitrile, a purifiedurethane compound of 483.60 g was obtained (Yield 75%).

[0158] The amounts of residual organic iron catalyst in the purifiedcompound were detected by absorptiometry.

[0159] The safety was evaluated by cytotoxicity test (colony assay). Themolecular weight was measured and lower molecular weight compounds weredetected by SEC. The results are shown in TABLES 5, and 6.

EXAMPLE B4 FeAA

[0160] A 100 g of the urethane compounds obtained by the same procedureas that of Example B3 was transferred to an extractor to remove thecatalyst and lower molecular weight compounds by using supercriticalcarbon dioxide gas providing 85.80 g of a purified urethane compound.The obtained purified compound was evaluated in the same procedure asthat of Example B3. The results are shown in TABLES 5, and 6.

EXAMPLE B5 FeBzAc

[0161] A urethane compound is prepared in the same procedure as that ofExample B3 except that 0.06 g of FeBzAc instead of FeAA, 22.30 g (0.10mole) of IPDI, 167.10 g of polydimethylsiloxane containing hydroxylgroups in its both ends (polymerization degree: 40, Hydroxyl groupequivalent: 1700 g/mole supplied by Aldrich, code name: KF-6002, made byShin-Etsu Chemical Co., Ltd.; DHDMSi-40), 11.80 g (0.10 mole) of HEA,and 0.06 g of p-methoxyphenol (MEHQ) as a polymerization inhibitor wereused providing 154.90 g (using acetonitrile, Yield 77%), 152.94 g (usingmethanol, Yield 76%) of a purified urethane compound. The obtainedpurified compound was evaluated in the same procedure as that of ExampleB3. The results are shown in TABLES 5, and 6.

EXAMPLE B6 FeAA

[0162] A purified urethane compound of 490.10 g (Yield 76%) was obtainedin the same procedure as that of Example B3 except that 87.70 g of4,4′-dicyclohexylmethandiisocyanate (DCHMDI) were used instead of IPDIas isocyanate compound. The obtained purified compound was evaluated inthe same procedure as that of Example B3. The results are shown inTABLES 5, and 6.

EXAMPLE B7 FeAA

[0163] A one-litter three-necked flask having a side tube equipped withDimroth reflux condenser, a mechanical stirrer and a thermometer waspreviously substituted with nitrogen gas and charged with 44.60 g (0.20mole) of IPDI and 0.07 g of FeAA. Then, the flask was charged with 90.80g of a polydimethylsiloxane containing hydroxyl groups in its both ends(polymerization degree: 10, Hydroxyl group equivalent: 1000 g/molsupplied by Aldrich, code name: KF-6001, made by Shin-Etsu Chemical Co.,Ltd.; hereinafter referred to as “DHDMSi-10”), heated in an oil bath at80° C., and stirred for about 4 hours. A part of the reaction mixturewas sampled for structural analysis to detect formation of anintermediate product with ¹H-NMR and FT/IR.

[0164] Then, the flask was charged with a solution of 0.07 g of FeAA and156.80 g of polyethylene glycol (Hydroxyl group equivalent: 1020 g/mole,supplied by Aldrich) in 200 ml of chloroform and refluxed for about 4hours. A part of the reaction mixture was sampled and stripped to removethe solvent under the reduced pressure in order to measure the hydroxylgroup equivalent (Acetylation method, 4210 g/mole).

[0165] A three necked flask charged with 106.50 g of the intermediateproduct was charged with 7.90 g (0.05 mole) of 2-isocyanatoethylmethacrylate (IEM). The three-necked flask was charged with 0.05 g ofMEHQ as a polymerization inhibitor, and stirred in an oil bath at 80° C.After about three hours, formation of a urethane compound was detectedwith ¹H-NMR and FT/IR.

[0166]¹H-NMR (in CDCl₃); δ0.06 (Si—CH₃, m), 0.52 (Si—CH₂, 2H, m), 2.91(NH—CH₂, 2H, d), 3.02 (CH₂—N═C═O, 2H, s), adjacent to 3.5 (—O—CH₂, m),4.18-4.34 (—(O)CO—CH₂—, 6H, m), 4.54 (NH, 1H, s), 4.85 (NH, 1H, s), 5.84(CH═, 1H, dd), 6.14 (CH═, 1H, dd), 6.43 (CH═, 1H, dd)

[0167] FT/IR: 1262 and 802 cm⁻¹ (Si—CH₃), 1094 and 1023 (Si—O—Si), 1632(C═C), adjacent to 1728 (C═O, ester and urethane)

[0168] A crude urethane compound obtained as above and dissolved in 1 Lof n-hexane was transferred to 5 L separatory funnel having a side tube.Then, the separatory funnel was charged with 200 mL of acetonitrile,stirred for 10 min at about 500 rpm, and then left to stand. Theacetonitrile phase was removed. The washing with acetonitrile wascarried out twice. The n-hexane phase was recovered and organic solventsand lower molecular weight compounds were stripped under reducedpressure. A purified urethane compound of 84.56 g was obtained (Yield74%).

[0169] The obtained purified compound was evaluated in the sameprocedure as that of Example B3. The results are shown in TABLES 5, and6.

EXAMPLE B8 FeAA

[0170] A one-litter three-necked flask having a side tube equipped withDimroth reflux condenser, a mechanical stirrer and a thermometer waspreviously substituted with nitrogen gas and charged with 4.46 g (0.020mole) of IPDI and 0.01 g of FeAA. Then, the flask was charged with 16.85g of a polydimethylsiloxane containing hydroxyl groups in its both ends(polymerization degree: 40, Hydroxyl group equivalent: 1700 g/molsupplied by Aldrich, code name: KF-6002, made by Shin-Etsu Chemical Co.,Ltd.; DHDMSi-40), heated in an oil bath at 80° C., and stirred for about4 hours. A part of the reaction mixture was sampled for structuralanalysis to detect formation of an intermediate product with ¹H-NMR andFT/IR.

[0171] Then, the flask was charged with a previously prepared solutionof 0.07 g of FeAA and 44.35 g of polyvinylpyrrolidone having hydroxylgroups and cationically crosslinkable group (2420 g/mole of hydroxylgroup equivalent) in 200 ml of chloroform, and refluxed for about 4hours. The polyvinylpyrrolidone was prepared by a thermal polymerizationof N-vinylpyrrolidone, 3-ethyl-3-allyloxymethyloxetane, and2-mercaptoethanol by using 2,2′-azobisisobutyronitrile (AIBN). A part ofthe reaction mixture was sampled to detect formation of a urethanecompound with ¹H-NMR and FT/IR.

[0172] A crude urethane compound obtained as above and dissolved in 500mL of n-hexane was transferred to 5 L separatory funnel having a sidetube. Then, the separatory funnel was charged with 50 mL ofacetonitrile, stirred for 10 min at about 500 rpm, and then left tostand. The acetonitrile phase was removed. The washing with acetonitrilewas carried out twice. The n-hexane phase was recovered and organicsolvents and lower molecular weight compounds were stripped underreduced pressure. A purified urethane compound of 43.20 g was obtained(Yield 72%).

[0173] The obtained purified compound was evaluated in the sameprocedure as that of Example B3. The results are shown in TABLES 5, and6.

EXAMPLE B9 ZnAA

[0174] The same procedure of EXAMPLE B1 was carried out except that195.0 g of perfluoropolyether (supplied by AUSIMONT JAPAN, and apolydimethylsiloxane containing hydroxyl groups in its both ends(polymerization degree: 40, Hydroxyl group equivalent: 1560 g/molesupplied by Aldrich, code name: KF-6002, made by Shin-Etsu Chemical Co.,Ltd.) was used instead of DHDMSi-40. The results are shown in TABLES 5,and 6.

COMPARATIVE EXAMPLE B1 ZnAA

[0175] A urethane compound was prepared providing 477.25 g (Yield 74%)of a purified urethane compound by the same procedure as that of ExampleB3 except that 0.09 g of ZnAA was used instead of FeAA. The sameprodecure was carried out except that methanol was used instead ofacetonitrile (Yield 67%, 432.13 g). The obtained purified compounds wereevaluated in the same procedure as that of Example B3. The results areshown in TABLES 5, and 6.

COMPARATIVE EXAMPLE B2 CuAA

[0176] A purified urethane compound of 451.40 g (Yield 70% usingacetonitrile for washing) or 399.87 g (Yield 62% using methanol forwashing) was obtained in the same procedure as that of ComparativeExample B1 except that 0.09 g of CuAA was used instead of ZnAA as acatalyst. The obtained purified compound was evaluated in the sameprocedure as that of Example B3. The results are shown in TABLES 5, and6.

COMPARATIVE EXAMPLE B3 BSnL

[0177] A purified urethane compound of 522.30 g (Yield 81% usingacetonitrile for washing) or 490.25 g (Yield 76% using methanol forwashing) was obtained in the same procedure as that of ComparativeExample B1 except that 0.08 g of BSnL was used instead of ZnAA as acatalyst. The obtained purified compound was evaluated in the sameprocedure as that of Example B3. The results are shown in TABLES 5, and6.

COMPARATIVE EXAMPLE B4 Triethylamine: TEA

[0178] A purified urethane compound of 279.30 g (Yield 70%) was obtainedin the same procedure as that of Comparative Example B1 except that 0.04g of TEA was used instead of ZnAA as a catalyst. The obtained purifiedcompound was evaluated in the same procedure as that of Example B3. Theresults are shown in TABLES 5, and 6. TABLE 5 Mn Mw/Mn Sub- No. Catalyst(SEC) (SEC. %) Product Appearance Cytotoxicity B1 FeAA 4400 1.38 NotTransparent Negative detected B2 FeTFPD 4500 1.38 Not TransparentNegative detected B3 FeAA 6100 1.41 0.7 Transparent Negative B4 FeAA6400 1.44 1.2 Transparent Negative B5 FeBzAc 6600 1.45 1.0 TransparentNegative B6 FeAA 6200 1.44 1.0 Transparent Negative B7 FeAA 8600 1.801.8 Transparent Negative B8 FeAA 14500  1.88 1.0 Transparent Negative B9FeAA 4100 1.47 Not Transparent Not tested detected Comp. ZnAA 7900 1.904.4 Transparent Not tested B1 Comp. CuAA 7700 1.70 4.0 Transparent Nottested B2 Comp. BSnL 6200 1.43 4.7 Transparent Positive B3 Comp. TEA10900  2.10 10.9  Transparent Negative B4

[0179] As mentioned above, a urethane compound was obtained by allcatalysts respectively, but, by a metal diketonate catalyst other thanan iron diketonate catalyst, the molecular weight was difficult to becontrolled and a large amount of sub-products was provided while thesafety was not cleared. In addition, by an amine catalyst, the safetywas high, but the molecular weight was difficult to be controlled, and alarge amount of sub-products was provided. Therefore, only by using aniron diketonate catalyst, the molecular weight was easily controlled aswell as the safety was high. TABLE 6 Yield Residual No. CatalystSolvents (%) catalyst (ppm) Ex. B1 FeAA hexane/CH₃CN 86 Not detected Ex.B2 FeTFPD hexane/CH₃CN 85 Not detected Ex. B3 FeAA hexane/CH₃CN 81 Notdetected hexane/CH₃OH 75 Not detected Ex. B4 FeAA Super critical CO₂ 86Not detected Ex. B5 FeBzAc hexane/CH₃CN 77 Not detected hexane/CH₃OH 76Not detected Ex. B6 FeAA hexane/CH₃CN 81 Not detected Ex. B7 FeAAhexane/CH₃OH 74 Not detected Ex. B8 FeAA hexane/CH₃OH 72 Not detectedEx. B9 FeAA hexane/CH₃CN — Not detected Comp. B1 ZnAA hexane/CH₃CN 74 90 hexane/CH₃OH 67  40 Comp. B2 CuAA hexane/CH₃CN 70 110 hexane/CH₃OH62 120 Comp. B3 BSnL hexane/CH₃CN 81  40 hexane/CH₃OH 76 Not testedComp. B4 TEA hexane/CH₃CN 70 Not detected

[0180] By using a metal acetylacetonate other than iron diketonate, thereaction time was elongated due to the low reactivity, and the yield waslow after extraction with organic solvents. The facts indicate that lowmolecular weight impurities were presented in the crude products in alarge amount. Further, deference in the amount of the residual catalystwas apparent (TABLE 5).

[0181] From the above-mentioned facts, the process using iron diketonatehaving low toxicity can decrease the amount of the residual catalyst andtherefore the process is a safety process.

[0182] (C) Production of Ocular Lens

[0183] Ocular lenses were produced as follows by using theabove-mentioned urethane compounds. Hereinafter, “% by weight” isreferred to as “%”.

EXAMPLE C1 Production of Oxygen Permeable Hard Lens

[0184] Ten % of the urethane compound produced in Example B1, 40% oftris(trimethylsiloxy)silylpropylmethacrylate (TRIS), 10% oftrifluoromethylmethacrylate (TFMA), 20% of methylmethacrylate (MMA), 10%of ethylene glycol dimethacrylate (EDMA), and 0.20% of2,2-azobis-(2,4-dimethylvaleronitorile) (V-65) were mixed to provide amixture solution. The mixture solution was filtrated, andfreeze-degassed. A test tube made of glass and having the diameter of 13mm and the length of 500 mm was charged with the mixture solution andtightly stoppered. The test tube was heated at 35° C. to 110° C. to curethe mixture solution providing a polymer rod. An ocular lens wasobtained by machining the obtained polymer rod.

EXAMPLE C2 Production of Oxygen Permeable Hard Lens

[0185] Ten % of the urethane compound produced in Example B3, 50% oftris(trimethylsiloxy)silylstyrene (SiSt), 10% of TFMA, 20% of MMA, 10%of vinylbenzylmethacrylate (VBMA), and 0.20% of V-65 were mixed toprovide a mixture solution. The mixture solution was filtrated, andfreeze-degassed. A test tube made of glass with the diameter of 13 mmand the length of 500 mm was charged with the mixture solution andtightly stoppered. The test tube was heated at 35° C. to 110° C. to curethe mixture solution and to provide a polymer rod. An ocular lens wasobtained by maching the obtained polymer rod.

EXAMPLE C3 Production of Oxygen Permeable Hard Lens

[0186] Twenty % of the urethane compound produced in Example B7, 70% ofMMA, 10% of EDMA, and 0.20% of V-65 were mixed to provide a mixturesolution. The mixture solution was filtrated, and freeze-degassed. Atest tube made of glass with the diameter of 13 mm and the length of 500mm was charged with the mixture solution and tightly stoppered. The testtube was heated at 35° C. to 110° C. to cure the mixture solution and toprovide a polymer rod. An ocular lens was obtained by machining theobtained polymer rod.

EXAMPLE C4 Production of Oxygen Permeable Soft Lens

[0187] Forty % of the urethane compound produced in Example B1, 40% ofDMA, 20% of MMA, and 0.20% of V-65 were mixed to provide a mixturesolution. The mixture solution was filtrated, and freeze-degassed. Atest tube made of glass with the diameter of 13 mm and the length of 500mm was charged with the mixture solution and tightly stoppered. The testtube was heated at 35° C. to 110° C. to cure the mixture solution and toprovide a polymer rod. The polymer rod was machined to form lens shapeand immersed in saline and autoclaved at 121° C. for 20 minutes toprovide an ocular lens.

EXAMPLE C5 Production of Oxygen Permeable Soft Lens

[0188] Sixty % of the urethane compound produced in Example B3, 40% ofDMA, 0.1% of 2-hydroxy-2-methyl-1-phenylpropane-1-on, 0.5% pf EDMAand0.02% tetra-(4-methacrylamide) copper phthalocyanine (APMA) were mixedto provide a mixture solution. The mixture solution was filtrated, andfreeze-degassed. A lens mold made of polypropylene was charged with themixture solution. The mixture solution was irradiated with UV light of10 mW/cm² and 365 nm for 30 minutes to be cured and to provide a lens.The lens was extracted in 2-propanol, and then treated with an autoclaveto provide an ocular lens after 2-propanol was replaced with saline.

EXAMPLE C6 Production of Oxygen Permeable Soft Lens

[0189] An ocular lens was obtained in the same procedure as that ofExample C5 except that 50% of the urethane compound obtained in ExampleB3, 20% of TRIS, 30% of DMA, 0.1% of2,4,6-trimethylbenzoyl-diphenylphosphine oxide (TPO), 0.1%-of2-(5-chloro-2H-benzotriazol-2-yl)-6-(1,1-dimethylethyl)-4-methylphenol(CBDMP), 0.5% of EDMA and 0.02% of APMA were used as components for themixture solution, and a lamp for UV light of 7.5 mW/cm² (405 nm) wasused.

EXAMPLE C7 Production of Oxygen Permeable Soft Lens

[0190] An ocular lens was obtained in the same procedure as that ofExample C6 except that 30% of the urethane compound obtained in ExampleB3, 30% of TRIS, 20% of N-vinyl-2-pyrrolidone (NVP), 20% of DMA, 0.1% ofTPO, 0.1% of CBDMP, 0.5% of EDMA and 0.02% of APMA were used ascomponents for the mixture solution.

EXAMPLE C8 Production of Oxygen Permeable Soft Lens

[0191] An ocular lens was obtained in the same procedure as that ofExample C6 except that 25% of the urethane compound obtained in ExampleB3, 25% of TRIS, 25% of N-methyl-3-methylene-2-pyrrolidone (MMP), 25% ofDMA, 0.1% of TPO, 0.1% of1-(4,6-diphenyl-1,3,5-triazine-2-yl)-5-(hexyloxy)phenol(DPTHP), 0.1% ofEDMA and 0.02% of APMA were used as components for the mixture solution.

EXAMPLE C9 Production of Oxygen Permeable Soft Lens

[0192] An ocular lens was obtained in the same procedure as that ofExample C6 except that 25% of the urethane compound obtained in ExampleB3, 25% of TRIS, 25% of NVP, 25% of acryloylmorpholine (ACMO), 0.1% ofTPO, 0.1% of DPTHP, and 0.02% of APMA were used as components for themixture solution.

EXAMPLE C10 Production of Oxygen Permeable Soft Lens

[0193] An ocular lens was obtained in the same procedure as that ofExample C6 except that 70% of the urethane compound obtained inExperiment B7, 30% of DMA, 0.1% of TPO, 0.1% of CBDMP, 0.5% of EDMA and0.02% of APMA were used as components for the mixture solution.

EXAMPLE C11 Production of Oxygen Permeable Soft Lens

[0194] An ocular lens was obtained in the same procedure as that ofExample C5 except that 90% of the urethane compound obtained in ExampleB8, 10% of 1,3-bis(3-ethyloxetanylmethoxypropyl)disiloxane, and 2.0% ofa boron-based cationic catalyst (a solution of 20% ofethanol/tetraarylboron salt in 2-propanol) were used as components forthe mixture solution.

[0195] Various measurements were carried out in accordance with thefollowing methods, respectively.

[0196] (I) Evaluation of Transparency

[0197] The test sample was observed with naked eye.

[0198] (II) NMR Analysis

[0199] The reactions were examined by NMR analysis on the reactionintermediates, the crude products, and the purified products under thesame conditions as in EXAMPLE A1.

[0200] (III) FT/IR Analysis

[0201] Chemical structures were identified by FT/IR analysis on thecrude products and purified products under the same conditions as inEXAMPLE 1.

[0202] (IV) SEC Analysis

[0203] A molecular weight and a molecular weight distribution weremeasured on the crude products and the purified products under the sameconditions as in EXAMPLE. Low molecular weight compounds were detectedfrom chromatograms.

[0204] (V) GC/MS Analysis

[0205] Chemical structures were analyzed under the following conditions.

[0206] Analyzer: G1800 made by Hewlett Packard

[0207] Column: HP-1 made by Hewlett Packard

[0208] Conditions: Injection temperature of 320° C., Oven temperature of50 to 300° C. (20° C./min), Detector temperature of 280° C., Sprit ratioof 50/1

[0209] (VI) Biological Safety Test: Cytotoxicity Test (Colony Assay)

[0210] The test was carried out in accordance with “the guideline ofBasic biological test of medical instruments and medical materials”(MEDICAL DEVICES DIVISION PHARMACEUTICAL AFFAIRS BUREAU Notification No.99, 1995, published on Jun. 27, 1995 in Japan).

[0211] (VII) Quantitative Analysis of Metal by an (Atomic) Absorptimetry

[0212] The extract with octane from the solution which was mixed withthe urethane compound and acids and heated was measured by GF atomicabsorption spectrometer. Concentrations were calculated from theobtained absorbances and a calibration curve.

What is claimed is:
 1. A process for preparing an ocular lens with aurethane compound comprising the steps of a) preparing a urethanecompound by reacting at least one hydroxyl compound and at least oneisocyanate compound in the presence of an organic iron compound, b)removing the organic iron compound from the urethane compound obtainedin the step a) c) mixing the urethane compound obtained in the step b)with at least one compound selected from the group consisting of anothercopolymerizable compound, a crosslinking agent, a UV absorbent, a dye, apolymerization initiator, a photosensitizer, and an organic solvent toobtain a mixture, and d) curing the mixture obtained in the step c) toprepare a lens.
 2. The process for preparing an ocular lens of claim 1wherein the organic iron compound is represented by the followingformula (I)

in which each of R¹ and R² is independently selected from the groupconsisting of methyl group, trifluoromethyl group and phenyl group. 3.The process for preparing an ocular lens of claim 1 wherein the organiciron compound is removed by using an organic solvent or a supercriticalfluid.
 4. The process for preparing an ocular lens of claim 1 whereinthe urethane compound obtained in the step b) has a radicalpolymerizable ethylenic unsaturated group or a photo cationiccrosslinkable functional group.
 5. The process for preparing an ocularlens of claim 1 wherein at least one of the hydroxyl compound or atleast one of the isocyanate compound has a siloxane structure having arepetition number of 1 to
 1500. 6. The process for preparing an ocularlens of claim 1 wherein at least one of the hydroxyl compound or atleast one of the isocyanate compound has a perfluoropolyether structurehaving a repetition number of 1 to
 1500. 7. The process for preparing anocular lens of claim 1 wherein at least one of the hydroxyl compound orat least one of the isocyanate compound has a hydrophilic polymerstructure having a molecular weight of 100 to
 1000000. 8. The processfor preparing an ocular lens of claim 7 wherein the hydrophilic polymerstructure has at least one structure obtained by polymerizing a monomerhaving a zwitterionic group such aspoly(2-methacryloyloxyethylphosphorylcholine).
 9. The process forpreparing an ocular lens of claim 7 wherein the hydrophilic polymerstructure consists of at least one compound selected from the groupconsisting of polyethylene glycol, polypropylene glycol,polyvinylalcohol, polyvinylpyrrolidone, poly(meth)acrylic acid, a saltof poly(meth)acrylic acid, poly 2-hydroxyethyl(meth)acrylate,polytetrahydrofuran, polyoxetane, polyoxazoline, polydimethylacrylamide,and polydiethylacrylamide.
 10. A process for preparing a urethanecompound for medical instruments, characterized by reacting a hydroxylcompound with an isocyanate compound in the presence of an organic ironcompound represented by the formula

in which each of R¹ and R² is independently selected from the groupconsisting of methyl group, trifluoromethyl group and phenyl group, as areaction catalyst to give a urethane compound.